• Because of their high energy requirements, neurons are especially vulnerable to injury and death from dysfunctional mitochondria.

• Pathological and physiological evidence reveals mitochondrial dysfunction in all major neurodegenerative diseases.

• Questions remain as to whether mitochondrial dysfunction is causal to neurodegenerative disease. Even if is not causal, mitochondrial dysfunction is still highly important and likely contributory to disease. Identifying therapies to improve mitochondrial function or to degrade dysfunctional mitochondria may make sense.

• Studying primary mitochondrial diseases can shed light on neurodegenerative diseases that show similar pathology. Because both types of diseases affect multiple pathways and organ systems, they require the approach of systems biology.

• Potential therapeutic approaches include medications that induce mitochondrial genesis, catalytic antioxidants to protect against reactive oxygen species, regulators of intracellular calcium, and regulators of redox potential across mitochondrial membrane. Maintenance of redox potential is crucial for mitochondrial integrity and control over oxidative phosphorylation.

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5
Mitochondrial Pathology
Key Points Raised by Individual Speakers
• Because of their high energy requirements, neurons are espe-
cially vulnerable to injury and death from dysfunctional
mitochondria.
• Pathological and physiological evidence reveals mitochondrial
dysfunction in all major neurodegenerative diseases.
• Questions remain as to whether mitochondrial dysfunction
is causal to neurodegenerative disease. Even if is not causal,
mitochondrial dysfunction is still highly important and likely
contributory to disease. Identifying therapies to improve mito-
chondrial function or to degrade dysfunctional mitochondria
may make sense.
• Studying primary mitochondrial diseases can shed light on neu-
rodegenerative diseases that show similar pathology. Because
both types of diseases affect multiple pathways and organ
systems, they require the approach of systems biology.
• Potential therapeutic approaches include medications that
induce mitochondrial genesis, catalytic antioxidants to protect
against reactive oxygen species, regulators of intracellular cal-
cium, and regulators of redox potential across mitochondrial
membrane. Maintenance of redox potential is crucial for mito-
chondrial integrity and control over oxidative phosphorylation.
45

OCR for page 45
46 NEURODEGENERATION
Mitochondria are cellular organelles responsible for oxidative phos-
phorylation, the vital process of converting nutrients into adenosine triphos-
phate (ATP) molecules that provide the power for normal cell functions.
Each neuron has at least hundreds of mitochondria. Because nerve cells are
postmitotic, any mitochondrial damage that is sustained will accumulate
with age and lead to dysfunction. Widespread damage to mitochondria
causes cells to die because they can no longer produce enough energy.
Indeed, mitochondria themselves unleash the enzymes responsible for cell
death. The brain is especially vulnerable to mitochondrial dysfunction
because its energy needs are higher than that of any other organ in the
body. The brain accounts for only 2 percent of body weight yet consumes
20 percent of oxygen.
Mitochondrial functioning is determined by two separate genomes,
one in the mitochondria, known as mitochondrial DNA (mtDNA), and the
other in the nucleus. The mitochondrial genome encodes 13 proteins, all of
which are vital to oxidative phosphorylation. The nuclear genome encodes
approximately 1,500 genes involved in mitochondrial biology, including
proteins necessary for replication of mtDNA, transcription, translation,
and posttranslational modifications. There is only one copy of mtDNA,
inherited from the mother, versus two copies of nuclear DNA, one from the
mother and the other from the father. Mitochondria not only are respon-
sible for oxidative phosphorylation, but they also play significant roles
in metabolism and signaling, including fatty acid synthesis, ketone body
metabolism, calcium homeostasis, and apoptosis. More specifically, mito-
chondria provide the majority of cellular energy in the form of ATP. They
generate and regulate reactive oxygen species, they buffer calcium levels
inside the cell, and they control apoptosis (Wallace, 2005, 2010).
Mitochondrial defects are found in pathological studies of all major
neurodegenerative diseases, said Vamsi Mootha of Harvard Medical
School. The range of mitochondrial defects includes fragmentation and
other morphological changes, increased mutation rates in mtDNA, changes
in permeability of mitochondrial membranes, changes in redox potential,
accumulation of mutant proteins, and impaired oxidative phosphorylation
(Reddy and Reddy, 2011). But whether these mitochondrial defects are
causal in neurodegenerative disease is the fundamental question, Mootha
said. The potential roles of mitochondria in neurodegenerative disease are,
in his view, threefold: (1) they harbor primary lesions and thus serve as the
primary source of disease pathology; (2) they function properly, but serve
as mediators or amplifiers of disease; or (3) they are bystanders that do not
contribute to pathology. Even if mitochondrial defects are not causal, they
are likely contributory, noted Neil Kowall of Boston University, and thus
any therapy that preserves, enhances, or corrects mitochondrial function
is likely to be beneficial in forestalling cell death and disease progression.

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MITOCHONDRIAL PATHOLOGY 47
This chapter summarizes workshop presentations that provide evidence
of mitochondrial dysfunction in major neurodegenerative diseases. Because
the evidence is unclear as to whether mitochondrial dysfunction is causal,
it may be valuable to look at primary mitochondrial diseases and adopt a
systems approach to research, several participants said.
Mitochondrial Dysfunction and
Neurodegenerative Diseases
As noted above, mitochondrial dysfunction is found in the major neu-
rodegenerative diseases. This section outlines workshop presentations about
mitochondrial dysfunction in Parkinson’s disease, amyotrophic lateral scle-
rosis (ALS), Huntington’s disease, and Alzheimer’s disease.
Parkinson’s Disease
Parkinson’s disease is characterized by a loss of dopamine-containing
neurons in the brain region known as the substantia nigra. Pathologi-
cal and other studies have convincingly shown that mitochondrial defi-
ciency accumulates in this brain region upon aging, said Richard Youle
of the National Institute of Neurological Disorders and Stroke. Youle’s
talk focused on the function of two proteins that are mutated in familial,
early-onset Parkinson’s disease: Parkin and PINK1 (PTEN-induced putative
kinase 1).
The normal functions of Parkin and PINK1 have not been well under-
stood until recently, Youle said. Evidence from multiple species is accumu-
lating that these proteins normally work together to trigger clearance of
damaged mitochondria, a process known as mitophagy. It stands to reason
that, if mutated, they can fail to induce mitophagy, leaving dysfunctional
mitochondria to accumulate within the cell and cause death. In this way, the
failure of mitophagy is implicated in the etiology of early-onset Parkinson’s
disease (Narendra and Youle, 2011).
When mitochondria are under stress or damaged, remarked Youle, they
accumulate PINK1. PINK1 is a mitochondrial protein ordinarily anchored
to the mitochondrion’s outer membrane at low concentrations. When the
mitochondrial membrane loses its electrical potential—whether by DNA
mutations, reactive oxygen species (ROS),1 or other perturbations—PINK1
increases. Increasing concentrations of PINK1, in turn, serve to recruit
Parkin, which is a ubiquitin ligase, from the cytosol. Parkin marks the
damaged mitochondrion with ubiquitin, a process that triggers formation
of an autophagosome (see also Chapter 3). The autophagosome engulfs
1 ROS are produced as a byproduct of oxidative phosphorylation.

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48 NEURODEGENERATION
the damaged mitochondrion, then merges with a lysosome, which degrades
it. The findings on PINK1/Parkin, which have been replicated in multiple
laboratories, have established a novel pathway for mitochondrion quality
control, said Youle. He noted that much of the earlier work in this area
was done on cultured cell lines, because the compounds used to induce this
pathway in cultured cell lines were too toxic to neurons. More recently,
however, two groups have shown the pathway in neurons (Cai et al., 2012;
Wang et al., 2011).
Youle relayed that his laboratory has started a drug screening program
to identify compounds that stimulate the PINK1/Parkin pathway. While
he acknowledged that people with early-onset Parkinson’s may not benefit
from stimulating the pathway because their PINK1 or PARKIN are mutated,
people with sporadic Parkinson’s disease may benefit, as might others with
neurodegenerative disease whose mitochondria are dysfunctional.
Amyotrophic Lateral Sclerosis
ALS predominantly affects motor neurons, leading to progressive mus-
cle wasting and paralysis. In animal models of ALS, mitochondrial abnor-
malities precede symptoms of disease (Manfredi and Xu, 2005). Electron
microscopy has revealed structural abnormalities in mitochondria in spinal
motor neurons and in the motor cortex of ALS patients. Neil Kowall of
Boston University focused his presentation on SOD1 (Cu, Zn superoxide
dismutase), the first identified gene responsible for causing ALS. The cor-
responding protein is mutated in about 20 percent of familial cases of ALS.2
The most widely used animal model of ALS is a transgenic mouse carrying
a mutant SOD1 gene. The mouse develops muscle wasting similar to that
of ALS.
Mitochondria from motor neurons in this animal model exhibit smaller
size, fewer number, defective membrane potential, and impaired fusion.
Fusion of mitochondria is designed to distribute mtDNA to the mito-
chondrial population and preserve the capacity for oxidative phosphoryla-
tion. These morphological and physiological changes in mutSOD1 motor
neurons are not seen in wild type SOD1 motor neurons (Magrane et al.,
2012). mutSOD1 also alters the levels of at least 50 different mitochondrial
proteins, including proteins involved in the electron transport chain and in
fusion, suggesting a possible widespread effect of mutSOD1 (Karbowski
and Neutzner, 2012).
mutSOD1 also inflicts mitochondrial damage, as assessed by an increase
of cytochrome c in the cytosol. Because cytochrome c is an essential com-
ponent of the electron transport chain, which is situated in the inner
2 About 5 to 10 percent of ALS cases are familial.

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MITOCHONDRIAL PATHOLOGY 49
membrane of the mitochondria, its release into the cytoplasm indicates
disruption of mitochondria membranes. But this toxic effect only occurs in
the presence of the protein Bcl-2, which can reverse its functional pheno-
type and become a toxic protein (Pedrini et al., 2010). The identification
of Bcl-2 as a necessary contributor to SOD1 toxicity suggests that Bcl-2
could be used as a molecular target for drugs designed to inhibit its action
(Pedrini et al., 2010). Bcl-2 may also be an important target not only in
familial ALS, but possibly also sporadic ALS, said Kowall. That is because
research has recently found that, in a subset of ALS patients with bul-
bar onset, wild-type SOD1 becomes hyperoxidized. In concert with Bcl-2,
hyperoxidized wtSOD1 displays mitochondrial toxicity similar to that seen
with mutSOD1. Thus, Bcl-2 represents a common link between familial
and a subtype of sporadic ALS, and thus appears to be a good target for
therapeutics that inhibit it.
Huntington’s Disease
Huntington’s disease is an autosomal dominant disease in which the
mutated protein, mhuntingtin (mHTT), displays excess polyglutamine
repeats. mHTT localizes to the outer mitochondrial membrane, where it
exerts widespread and deleterious effects on mitochondria and selective
loss of neurons in the striatum. Kowall said a great deal of evidence shows
that mHTT reduces mitochondrial motility, alters mitochondrial morphol-
ogy, causes calcium dysregulation, reduces oxidative phosphorylation, and
depolarizes the mitochondrial membrane in lymphoblasts of Huntington’s
disease patients. The depolarization is increased with greater numbers of
polyglutamine repeats. mHTT also alters the balance between mitochon-
drial fusion and fission (Lin and Beal, 2006; Reddy and Reddy, 2011).
Several therapeutic strategies have recently emerged for Huntington’s
disease, Kowall noted. One avenue is to target a mitochondrial fission3
protein to which mHTT binds, GTPase dynamin-related protein 1 (DRP1).
The targeting of DRP1 is suggested by the finding that a dominant-negative
DRP1K38A mutant, which reduces DRP1 activity, rescues mitochondria
from the following adverse effects of mHTT: mitochondrial fragmentation,
defects in anterograde and retrograde mitochondrial transport, and neu-
ronal cell death. These findings were reported in cells from humans with
Huntington’s disease and from mice (Song et al., 2011). In other words,
compounds that inhibit DRP1 might be useful as potential therapies.
Kowall described two more novel therapies. The first aims to detox-
3 Mitochondrial fission is a quality control mechanism in which the mitochondrion divides
into two, one healthy and the other containing the damaged portion of the mitochondria. The
latter portion is degraded.

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50 NEURODEGENERATION
ify HTT. It involves intraventricular infusion of ganglioside GM1, which
phosphorylates mutant HTT at specific serine amino acid residues. The
approach not only curtailed the toxicity of HTT, but also restored normal
motor function in symptomatic Huntington’s disease mice (Di Pardo et al.,
2012). The second therapy is with the already approved drug meclizine.
This drug suppresses mitochondrial respiration and activates cellular sur-
vival pathways. In several models of Huntington’s disease, meclizine was
found to be neuroprotective (Gohil et al., 2011).
Alzheimer’s Disease
Mitochondrial dysfunction precedes the pathological changes that are
the hallmarks of Alzheimer’s disease (Yao et al., 2009). Douglas Wallace
of the Children’s Hospital of Philadelphia proposed that the cause of
Alzheimer’s disease—and dementia more broadly—is from underlying dys-
function of the mitochondria. Beginning in 1993, Wallace’s team found a
mutation in one of the mitochondrial tRNA genes. The mutation correlated
with 3 percent of late-onset Alzheimer’s cases, 5 percent of Parkinson’s, and
7 percent of the combined population. The finding was later corroborated
by others. He asserted that subtle defects in tRNA will generate more global
mitochondrial protein synthesis defects. Subsequently, his team began to
study a mutation at the nucleotide position 414, which is adjacent to the
control region promoter of mtDNA. The mutation previously had been
shown to be increased with age in human fibroblasts (Michikawa et al.,
1999). Wallace’s team found the mutation in 65 percent of Alzheimer’s
brains and 57 percent of Down syndrome–dementia brains versus 0 percent
of age-matched controls (Coskun et al., 2004).
Most recently, Wallace’s team examined more globally the control
region of mtDNA in tissue taken from the frontal cortex of the brain. The
control region is responsible for regulating transcription of mitochondrial
genes and helps copy mtDNA. They found the highest rate of somatic
mutations in the Alzheimer’s brain (Coskun et al., 2010). The mutation
frequency was also elevated in Down syndrome–dementia cases relative to
controls, but it was lower than that in Alzheimer’s. Control tissue did show
an age-related increase in mutation frequency, although the level was lower
than that found in the other groups. The heightened rate of mutations was
also found in serum and other tissues of Alzheimer’s and Down syndrome
cases, suggesting that the phenomenon is systemic. But, said Wallace, the
brain is the most deeply affected tissue because of its disproportionately
high energy demands. The study also found reduction in transcription of
mtDNA and a reduction in the mtDNA copy number, implying a reduction
in oxidative phosphorylation.
Turning to causation of neurodegenerative disease, Wallace expressed

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MITOCHONDRIAL PATHOLOGY 51
the view that formation of Aβ plaques is not causal; rather, he hypoth-
esized, Aβ protein is initially produced by cells as a compensatory means
of protecting mitochondria. But as the protein continues to be produced,
it begins to aggregate to form oligomers and larger aggregates that inhibit
mitochondria, leading to cell injury and death. According to this model, the
protein aggregates are contributory to the death of neurons in neurodegen-
erative disease, but not causal. Primary causation, according to his hypoth-
esis, rests with dysfunctional mitochondria. He expressed the opinion that
“bioenergetics is the common pathophysiological mechanism for all of these
neurodegenerative diseases.” He was then questioned in the discussion by
several skeptical participants who did not agree with his causal attribution.
In reply, Wallace described how his team had developed a way to introduce
a cytochrome oxidase point mutation in mtDNA and found that the animal
developed cardiomyopathy, myopathy, and pathological changes in hippo-
campal neurons, in retinal ganglion cells, and in the optic nerve. “This one
particular point mutation—it has nothing to do with the nucleus—shows
that energetics can affect all of those different functions,” he asserted.
Protein Deposits and Toxicity to Mitochondria
Multiple lines of evidence suggest that toxic proteins such as Aβ, apo-
lipoprotein E (ApoE) fragments, and a-Synuclein can impair mitochon-
dria, said Lennart Mucke of the Gladstone Institutes and the University of
California at San Francisco. In this case, the damaged mitochondria would
not be the primary cause of the disease, but rather would be secondary
to the actions of aggregated proteins, which would be the primary cause.
A significant amount of research shows that Aβ peptide accumulates in
mitochondria, where they cause dysfunction and apoptosis (Manczak et
al., 2006; Yao et al., 2009).
One possible mechanism by which protein deposits are toxic to neu-
rons is by impairment of axonal transport of mitochondria. Mitochondria
are generated largely in the cell body and need to be actively transported
to the synapse, where energy need is high. Devoid of mitochondria, syn-
aptic function can be impaired. Mucke and his team assessed the effects
of Aβ and tau proteins on axonal transport of mitochondria (Vossel et al.,
2010). They found that adding Aβ oligomers in culture quickly inhibited
axonal transport of mitochondria in healthy neurons, a finding supported
by earlier research. They also were interested in determining whether tau
played a role. Reducing tau levels prevented Aβ oligomer-induced disrup-
tion of axon transport without affecting baseline axonal transport. The
complete elimination of tau by gene knockdown also had the same effect.
They concluded, “Aβ requires tau to impair axonal transport, and that tau

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52 NEURODEGENERATION
reduction protects against defects in Aβ-induced axonal transport” (Vossel
et al., 2010, p. 198-a).
Another disease-related protein that impairs mitochondria is ApoE.
The ApoE gene is the main susceptibility gene identified for late-onset
Alzheimer’s disease, and it is found on chromosome 19. Neurons produce
ApoE when they are stressed by a host of factors, including aging, oxida-
tive stress, trauma, and protein deposition. ApoE synthesis is thought to
protect neurons from damage and to repair and remodel them. However,
research has shown that the cleavage products of ApoE impair mitochon-
dria (Brecht et al., 2004). ApoE e4, the allele associated with Alzheimer’s
disease, is most sensitive to being cleaved, whereas the other ApoE alleles
are less so, said Mucke.
Mitochondrial Diseases and Their Utility
for Neurodegenerative Disease
Given the uncertainty as to what roles mitochondrial dysfunction plays
in neurodegerative disease, Mootha suggested the value of studying primary
mitochondrial diseases, which refer to nearly 150 genetic diseases in which
the lesion lies in a gene encoding a protein that is directly involved in mito-
chondrial biology. The diseases are heterogeneous, with dozens being the
focus of study over many decades. Caused by genetic single-gene mutations
or deletions, they follow Mendelian or a maternal pattern of inheritance.
Mitochondrial disease can shed light on neurodegenerative disease,
said Mootha, in part because disease phenotypes are similar. For example,
some mitochondrial disease phenotypes include ataxia, neuropathy, myop-
athy, deafness, and blindness. Indeed, several subsequent presentations
focused on mitochondrial pathology in neurodegenerative disease, such as
Parkinson’s and ALS. Another reason why mitochondrial diseases carry
import for neurodegenerative disease is that multiple organ systems are
involved, just like neurodegenerative diseases, and their genetics are better
characterized through an ambitious project known as the Mitocarta, which
is an inventory of more than 1,000 mouse genes encoding proteins that
localize to the mitochondria (Pagliarini et al., 2008). Finally, mitochondrial
diseases are valuable, in his view, in providing “genetic extremes” that can
help to determine whether or not a particular neurodegenerative disease
may have mitochondrial defects as the root cause. Mootha advised look-
ing for connections between mitochondrial and neurodegenerative diseases
when there is at least some common ground, such as in pathogenesis,
pathology, or biomarkers.
Even though mitochondria look similar upon microscopy, looks are
deceiving. Mootha remarked on the enormous heterogeneity of mitochon-
dria across different tissues. He reported that, after studying 14 different

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MITOCHONDRIAL PATHOLOGY 53
tissues, research has found that mitochondria from 2 different tissues share
only 75 percent of their proteins, whereas the remaining mitochondrial pro-
teins are tissue specific. There is even physiological heterogeneity within an
individual cell—mitochondria, for example, can possess different patterns
of fuel usage. Given the diversity of phenotypes and genotypes, Mootha
advocated for a systems approach to the study of mitochondrial function.
Such an approach combines genomics, proteomics, metabolomics, biochem-
istry, and computer modeling to capture the dynamic range of complex
interactions within cells and across tissues. Applying systems biology to
neurodegenerative diseases would require identifying component parts,
building wiring diagrams to connect these parts, identifying circuitry causal
for the disease, and using the knowledge to develop therapies, he observed.
Mitochondria and Cell Death
One commonality across neurodegenerative diseases is that they all
feature a high degree of cell death. Here the focus is on mitochondria;
mitochondria play a key role in regulating cell death, which occurs in
specific brain regions across all neurodegenerative diseases. Cell death is
of three types: (1) necrosis, which is the most chaotic form of death that
involves cytoplasmic swelling, nuclear dissolution, and lysis; (2) apoptosis,
an orderly form of death, reliant on ATP, that produces cell fragments that
phagocytic cells are able to engulf and remove before the cell’s contents
disgorge onto surrounding cells and cause damage; and (3) autophagy, in
which the cell degrades its cytoplasm and organelles via lysosomes (Martin
et al., 2010). Mitochondria are the sites where antiapoptotic and proapop-
totic proteins interact, and they regulate signals for cell death.
Lee Martin of Johns Hopkins University cautioned that cell death in
humans versus animal models of neurodegenerative diseases may not be by
similar mechanisms. He reported mouse–human species differences in the
factors controlling the mitochondrial permeability transition (MPT), that is,
an increase in permeability of mitochondrial membranes to small molecular
weight molecules. MPT results from opening the mitochondrial perme-
ability transition pore, a protein pore formed in mitochondrial membranes
under certain pathological conditions. Induction of the permeability tran-
sition pore can lead to swelling of mitochondria and necrosis, and it also
plays a major role in some types of apoptosis. Martin also noted species
differences in signaling mechanisms of caspases, which are enzymes under
the control of the mitochondria that are crucial to apoptosis, differences
in caspace substrates, differences in mitochondrial fusion machinery, and
in signaling mechanisms for DNA repair and metabolism, among others.
Species differences in cell death confound the translation of findings from
animal models into human clinical trials, he observed. He suggested modi-

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54 NEURODEGENERATION
fying the design of preclinical studies to rely less on mouse as models and
more on human neural stem cell–derived neurons.
Potential Biomarkers and Therapies
There are no established biomarkers or therapies for treating mito-
chondrial dysfunction in neurodegenerative disease. Wallace said his labo-
ratory is working to develop them. One biomarker under development is
near-infrared spectroscopy across the skin, using different infrared diodes
that interrogate the redox potential of the respiratory chains. Wallace said
his laboratory is also developing a biomarker using micro-organic breath
analysis. They are hoping to get some surrogate variables that change in
real time, and then go into a Phase I clinical trial and have at least a safety/
efficacy indication.
Regarding therapies, this chapter has already mentioned a few in rela-
tion to specific neurodegenerative diseases. Focusing instead on generic
therapies for mitochondrial dysfunction, Wallace said his first priority for
therapy would be to stimulate formation of more mitochondria. Drugs to
generate mitochondria are being tested in various animal models and cell
culture systems. In particular, he noted that the drug bezafibrate has been
found to increase mitochondrial biogenesis in cancer cells and ameliorate
mitochondrial dysfunction (Wang and Moraes, 2011). It has not yet been
tested in brain cells.
Other therapeutic options, Wallace explained, include (1) catalytic
antioxidants to protect against ROS; (2) regulators of intracellular calcium;
and (3) regulators of redox potential across mitochondrial membrane.
Maintenance of redox potential is crucial for mitochondrial integrity and
control over oxidative phosphorylation. One participant pointed out that
antioxidant therapies have been uniformly ineffective in clinical trials, but
Wallace responded that the doses may have not been high enough. Another
participant advised targeting mitochondrial therapies in cases of threshold
effects, that is, the point at which there is significant compromise of mito-
chondrial function. The participant also noted the possibility of mitochon-
drial therapies having secondary downsides.
Research Needs and Next Steps Suggested
by Individual Participants
The workshop speakers identified many questions for future research
and other opportunities for future action. The suggestions related to mito-
chondrial dysfunction are compiled here to provide a sense of the range
of suggestions made. The suggestions are identified with the speaker who

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MITOCHONDRIAL PATHOLOGY 55
made them and should not be construed as reflecting consensus from the
workshop or endorsement by the Institute of Medicine.
• Develop deeper understanding of energy biology and interactions
between bioenergetics and environmental influences. (Wallace)
• Identify biomarkers to follow mitochondrial functioning. (Lee,
Mootha)
• Find biomarkers of mitochondrial decline. (Mootha)
• Identify new therapies that increase mitochondrial biogenesis.
(Wallace)
• Identify therapies that interfere with mitochondrial contribution
to pathogenesis of neurodegenerative disease, including therapies
that increase mitophagy or stimulate activity of PINK1 and Parkin.
(Mootha, Youle)
• Find therapies that detoxify mutant protein aggregates that interact
with mitochondria. (Kowall)